This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The longterm goal of this study is to understand the role of viral immune modulators for monkeypox virus (MPV) virulence. Individuals infected with MPV during the 2003 outbreak developed a strong MPV-specific T cell response, but the MPV-specific T cells were not stimulated by MPV-infected antigen presenting cells (APC) in vitro. In contrast, infection of APC by the vaccine strain Vaccinia-virus (VV) WR activated cross-reactive CD8+ and CD4+ T cells from MPV-infected individuals. These data strongly suggest that MPV prevents T cell stimulation by expressing immunomodulators that are absent in VV. In this application we will test this hypothesis by a) determining whether MPV downregulates MHC class I molecules, b) identifying the viral inhibitor of antigen presentation (VIPR) of MPV, and c) generating VIPR-deleted MPV and examining whether this recombinant virus activates MPV- specific T cells from MPV-infected humans and non-human primates (NHP). Upon completion of this exploratory project we plan to address the role of this immune modulatory mechanism for pathogenesis of MPV in NHP and for the ability of MPV to escape vaccine-induced cellular immunity.